Flavorings in liquids used in electronic nicotine delivery systems (ENDS) are a largely unrecognized potential respiratory hazard. There are thousands of such flavors in commercial use in ENDS, including a large proportion of sweet or creamy flavored ENDS solutions (among the most popular flavorings), used in marketing to children and emerging adults. Several diketone compounds (including diacetyl and 2,3-pentanedione), which are generally recognized as safe for ingestion, are commonly used in food products to give them a buttery or creamy flavoring, and have recently been shown to be present in sweet-flavored ENDS solutions. When inhaled, high doses of these diketones cause acute-onset bronchiolitis obliterans (popcorn lung), a severe and irreversible obstructive lung disease. In the only published study to measure diacetyl or 2,3-pentanedione in ENDS flavorings, these compounds were found to be present in 75% of 159 `sweet flavored' ENDS solutions. However, awareness of this problem is virtually absent from the public health and regulatory discussion of the impact of flavorings on ENDS users, and there has been little study of the pulmonary toxicity of flavorings used in ENDS products, although ENDS are designed to create an ultrafine aerosol that penetrates deeply into the lung. We propose to evaluate the respiratory effects associated with use of sweet- flavored ENDS in 60 users (children and emerging adults) of flavored ENDS solutions likely to contain diketones. We hypothesize that concentrations of diketones in sweet-flavored ENDS will predict adverse acute and subacute effects of ENDS on markers of respiratory health. Acute respiratory effects of using flavored ENDS solutions will be evaluated after a regulated, 5 minute `challenge' with each subject's ENDS solution in a laboratory setting, following a one-week run-in period with a standard ENDS solution without flavor (Specific Aim 1a). Subacute (week-long) respiratory effects will be evaluated after one week of flavored ENDS use (Aim 1b). Outcomes will include potential systemic biological markers of lung damage, including serum levels of club cell secreted protein (CCSP), AREG, and IL-8; and markers of airway inflammation [(fractional excretion of nitric oxide (FeNO)], and of functional changes in FEV1 and FVC. In Aim 2, we will estimate each individual's inhaled dose, based on concentrations of diacetyl and 2,3-pentanedione in each subject's solution, volume of solution used, repeated serum cotinine, and innovative use of data from the Smokio Smart Vaping ENDS, which uses an automatic system to record timing, number, and intensity of puffs using a chip within the ENDS that synchronizes data collection to the user's smartphone. Aim 3 will examine the diketone dose-response relationship to adverse respiratory health markers. Diacetyl and related diketone flavorings in ENDS are potentially a major public health threat to children because of widespread use and known respiratory toxicity. Assessment of acute and subacute effects is essential to characterizing this hazard, to the design of subsequent studies to investigate chronic effects, and to evaluation of the need for regulatory intervention.